C1GALT1C1

protein-coding

C1GALT1 specific chaperone 1

Gene summary

This gene encodes a type II transmembrane protein that is similar to the core 1 beta1,3-galactosyltransferase 1, which catalyzes the synthesis of the core-1 structure, also known as Thomsen-Friedenreich antigen, on O-linked glycans. This gene product lacks the galactosyltransferase activity itself, but instead acts as a molecular chaperone required for the folding, stability and full activity of the core 1 beta1,3-galactosyltransferase 1. Mutations in this gene have been associated with Tn syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2009]

MANE transcript

NM_001011551.3

Inheritance

ClinVar variants

P:8U:49B:14

Top phenotype

Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:120,625,674-120,630,054

External References & Databases

Ensembl (ENSG00000171155)

Transcript & Mutation Effects

hg38 • Region Span ~4.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemolytic uremic syndrome, atypical, 8, with rhizomelic short statureLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0957495

Submitter: ClinGen

C1GALT1C1 was first reported in relation to x-linked atypical hemolytic uremic syndrome 8 with rhizomelic short stature (AHUS8) in 2023 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). C1GALT1C1 (also known as COSMC) is a highly evolutionary conserved gene mapped to chromosome Xq24 (Hadar et al., PMID: 36599939). It is a molecular chaperone required for the proper folding and full activity of T synthase, the enzyme that initiates complex O-glycans biosynthesis (Erger et al., PMID: 37216524). In humans, somatic loss-of-function variants in C1GALT1C1 have been associated with Tn polyagglutination syndrome. Two recent reports, including a de novo hemizygous missense mutation and a hemizygous germline loss of function variant have been reported to cause AHUS8 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). The term COSMC-CDG has been suggested (Erger et al., PMID: 37216524). Common symptoms among the reported cases include a combination of thrombocytopenia, immune deficiency, developmental delay, short stature with short limbs, facial dysmorphisms and variable-onset acute kidney injury resembling aHU in hemizygous males. Females exhibit less pronounced clinical phenotypes in line with X-linked semidominant inheritance. Treatment with C5 inhibitors results in improvement of renal function (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). This gene-disease relationship is supported by relevant experimental evidence, including an animal model (Wang et al., PMID:20439703) and expression studies (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). Currently, the biological evidence is clear but more clinical evidence is necessary. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on January 2, 2025 (SOP Version 11).

hemolytic uremic syndrome, atypical, 8, with rhizomelic short statureLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0957495

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hemolytic uremic syndrome, atypical, 8, with rhizomelic short statureXL

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Hematologic; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Renal

Rationale: The condition can involve multi-systemic manifestations, and in addition to managing cardiovascular, infectious, hematologic, and renal complications, medical management (eg, with C5 inhibitor eculizumab) has been described as beneficial

Refs: 36599939; 37216524

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C1GALT1C1 variants in ClinVar

7 Conditions Cataloged

Polyagglutinable erythrocyte syndromeTotal: 30

not specifiedTotal: 24

Hemolytic uremic syndrome, atypical, 8, with rhizomelic short statureTotal: 5

not providedTotal: 3

C1GALT1C1-related disorderTotal: 2

Atypical hemolytic-uremic syndromeTotal: 1

Abnormal protein O-linked glycosylationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001011551.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	10 clinvar		11
missense	3 clinvar	2 clinvar	46 clinvar	2 clinvar	2 clinvar	55
nonsense	2 clinvar					2
start loss	1 clinvar					1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	6	2	49	12	2	71

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001011551.3	RefSeq	NP_001011551.1	1	MANE Select
ENST00000304661.6	Ensembl	ENSP00000304364.5	1	MANE Select
NM_152692.5	RefSeq	NP_689905.1	1	Standard
ENST00000371313.2	Ensembl	ENSP00000360363.2	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mucin type O-glycan biosynthesis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
O-linked glycosylation of mucins
O-linked glycosylation

Biological Process

protein O-linked glycosylation
O-glycan processing, core 1
platelet activation
platelet morphogenesis

Molecular Function

protein binding
glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase activity

Cellular Component

Golgi membrane
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304661
Coding exons: 1
Length: 4358
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.03	84	115	0.730	0.00000798	2145
Missense (PolyPhen)		17	34.134	0.49804		672
Synonymous	0.0563	38	38.4	0.988	0.00000263	568
Loss of Function	2.32	0	6.26	0.00	4.50e-7	129

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable chaperone required for the generation of 1 O- glycan Gal-beta1-3GalNAc-alpha1-Ser/Thr (T antigen), which is a precursor for many extended O-glycans in glycoproteins. Probably acts as a specific molecular chaperone assisting the folding/stability of core 1 beta-3-galactosyltransferase (C1GALT1). {ECO:0000269|PubMed:12464682}.;

Recessive Scores

pRec: 0.145

Intolerance Scores

RVIS EVS: 0.53
RVIS percentile EVS: 80.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium